Ryvu Therapeutics discovers and develops small molecule therapies that address high value emerging targets in oncology.
Our pipeline is built from internally-discovered candidates which make use of diverse therapeutic mechanisms, including programs directed at targets in the areas of transcriptional regulation, synthetic lethality, immuno-oncology and immunometabolism.
Ryvu’s two most advanced programs are currently in clinical trials. SEL120 is a selective CDK8 kinase inhibitor in clinical development for the treatment of acute myeloid leukemia and high-risk myelodysplastic syndromes.
SEL24/MEN1703 is a dual PIM/FLT3 kinase inhibitor in clinical development for the treatment of acute myeloid leukemia. Additional programs include candidates directed at SMARCA2/BRM, adenosine A2A/A2B receptor targets and STING agonists.
CDK8 is a kinase submodule of the mediator complex, involved in both transcriptional activation and repression. CDK8- mediator complex integrates basal transcriptional machinery with the activity of oncogenic transcriptional and epigenetic factors. Targeting CDK8 and...
SEL24/MEN1703 is a clinical stage program discovered and developed by Ryvu and licensed to the Menarini Group. SEL24/MEN1703 is a first-in-class, dual PIM/FLT3 kinase inhibitor with a unique activity profile. By design, this profile may...
CDK8 is a kinase submodule of the mediator complex, involved in both transcriptional activation and repression. CDK8- mediator complex integrates basal transcriptional machinery with the activity of oncogenic transcriptional and epigenetic factors. Targeting CDK8 and its paralog CDK19 using potent and selective CDK8 inhibitor SEl120 may be an effective way for treatment of both hematological malignancies and solid tumors with deregulated transcription. Functional studies defined CDK8 as a regulator of paracrine activities of cancer cells, hypoxia response network and other pathways including the p53 network, the Wnt–β-catenin pathway, the Notch1, JAK/STAT1 signaling, and pathways regulated by SMAD TFs. Because of the established role in repression of NK cell cytotoxicity and tumor surveillance, CDK8 inhibitors may also have utility as an immunooncology treatment. In March 2019 Ryvu received approval from the U.S. Food and Drug Administration to initiate a Phase 1b study for its SEL120 program in acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (HR-MDS) and first patient was dosed in September 2019.
- SEL120 is a selective CDK8/CDK19 inhibitor in Phase I in patients with AML/ HR-MDS (NCT04021368)
- SEL120 treatment results in on-target efficacy in preclinical models of AML in vitro and in vivo
- Inhibition of CDK8 can repress key oncogenic transcriptional programs and induce lineage commitment genes in AML
- CDK8 and CDK19 are also preclinically validated novel targets for the treatment of breast and prostate cancers
- There are no competitive CDK8/19 inhibitors actively tested in clinical trials
- SEL120 is a clinical stage highly specific and orally bioavailable dual CDK8/CDK19 inhibitor
- First patient dosed in Phase 1b trial in AML and HR-MDS in August 2019
- Demonstrated high on-target efficacy, including complete regressions in preclinical models of AML
- Efficacy in leukemia cells linked with induction of apoptotic cell death and induction of differentiation
- Demonstrated synergy with standard of care and late stage development candidate drugs in AML
- Specific inhibition of CDK8/19 biomarkers correlates with efficacy in responder cells in the low nM range
- On-target transcriptional changes in cancer cells with SEL120, including inhibition of oncogenic gene expression patterns and induction of lineage commitment genes
- Bioinformatic analysis of treated cells allowed for in-depth understanding of a link between molecular mode of action and response in cancer cells
- Differential efficacy of SEL120 demonstrated also in breast cancer, Willms tumors, Lymphomas and colorectal cancer models in vitro and in vivo
- Synergy of SEL120 with anti-PD1 antibodies in immunooncology in vivo models
- SEL120 treatment effectively increases reticulocyte and hemoglobin levels in models of a rare ribosomopathy – Diamond-Blackfan Anemia
- Partnership with The Leukemia & Lymphoma Society to co-fund and scientifically support further preclinical and clinical development of SEL120
- clinicaltrials.gov (https://clinicaltrials.gov/ct2/show/NCT04021368)
- Philip, Stephen, Malika Kumarasiri, Theodosia Teo, Mingfeng Yu, and Shudong Wang, ‘Cyclin-Dependent Kinase 8: A New Hope in Targeted Cancer Therapy?’, Journal of Medicinal Chemistry, 2017, acs.jmedchem.7b00901 https://doi.org/10.1021/acs.jmedchem.7b00901
- Roninson, Igor B., Balázs Győrffy, Zachary T. Mack, Alexander A. Shtil, Michael S. Shtutman, Mengqian Chen, and others, ‘Identifying Cancers Impacted by CDK8/19’, Cells, 8 (2019), 821 https://doi.org/10.3390/cells8080821
- Rzymski, Tomasz, Michał Mikula, Katarzyna Wiklik, and Krzysztof Brzózka, ‘CDK8 Kinase–An Emerging Target in Targeted Cancer Therapy.’, Biochimica et Biophysica Acta, 1854 (2015), 1617–29 https://doi.org/10.1016/j.bbapap.2015.05.011
- Rzymski, Tomasz, Michał Mikula, Eliza Żyłkiewicz, Agnieszka Dreas, Katarzyna Wiklik, Aniela Gołas, and others, ‘SEL120-34A Is a Novel CDK8 Inhibitor Active in AML Cells with High Levels of Serine Phosphorylation of STAT1 and STAT5 Transactivation Domains’, Oncotarget, 8 (2017), 33779–95 https://doi.org/10.18632/oncotarget.16810
- Nitulescu, Ioana I., Sara C. Meyer, Qiang Jeremy Wen, John D. Crispino, Madeleine E. Lemieux, Ross L. Levine, and others, ‘Mediator Kinase Phosphorylation of STAT1 S727 Promotes Growth of Neoplasms With JAK-STAT Activation’, EBioMedicine, 26 (2017), 112–25 https://doi.org/10.1016/j.ebiom.2017.11.013
- Pelish, Henry E, Brian B Liau, Ioana I Nitulescu, Anupong Tangpeerachaikul, Zachary C Poss, Diogo H Da Silva, and others, ‘Mediator Kinase Inhibition Further Activates Super-Enhancer-Associated Genes in AML.’, Nature, 2015 https://doi.org/10.1038/nature14904
- Xu, Dazhi, Chien-Feng Li, Xian Zhang, Zhaohui Gong, Chia-Hsin Chan, Szu-Wei Lee, and others, ‘Skp2-MacroH2A1-CDK8 Axis Orchestrates G2/M Transition and Tumorigenesis.’, Nature Communications, 6 (2015), 6641 https://doi.org/10.1038/ncomms7641
- McDermott, Martina S.J., Alexander A. Chumanevich, Chang Uk Lim, Jiaxin Liang, Mengqian Chen, Serena Altilia, and others, ‘Inhibition of CDK8 Mediator Kinase Suppresses Estrogen Dependent Transcription and the Growth of Estrogen Receptor Positive Breast Cancer’, Oncotarget, 8 (2017), 12558–75 https://doi.org/10.18632/oncotarget.14894
- Hsieh, Robert W, Angera H Kuo, Ferenc A Scheeren, Mark A Zarnegar, Shaheen S Sikandar, Jane Antony, and others, ‘CDK19 Is a Regulator of Triple-Negative Breast Cancer Growth’, BioRxiv, 2018 https://doi.org/https://doi.org/10.1101/317776
- Bra gelmann, J., N. Klu mper, Anne Offermann, A. von Ma ssenhausen, D. Bo hm, M. Deng, and others, ‘Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer’, Clinical Cancer Research, 2016 https://doi.org/10.1158/1078-0432.CCR-16-0094
- Witalisz-Siepracka, Agnieszka, Dagmar Gotthardt, Michaela Prchal-Murphy, Zrinka Didara, Ingeborg Menzl, Daniela Prinz, and others, ‘NK Cell-Specific CDK8 Deletion Enhances Antitumor Responses’, Cancer Immunology Research, 2018, canimm.0183.2017 https://doi.org/10.1158/2326-6066.CIR-17-0183
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- Acute Myleoid Leukemia
- A Phase Ib Study of SEL120 in Patients With Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome
SEL24/MEN1703 is a clinical stage program discovered and developed by Ryvu and licensed to the Menarini Group. SEL24/MEN1703 is a first-in-class, dual PIM/FLT3 kinase inhibitor with a unique activity profile. By design, this profile may provide responses to treatment that are more durable than current options and address disease that has progressed following FLT3 inhibition. SEL24/MEN1703 is initially being developed for the treatment of patients with relapsed/refractory acute myeloid leukemia. Preclinical data suggests therapeutic potential in other hematological malignancies and in solid tumors. Ryvu has granted the Menarini Group an exclusive worldwide license to further research, develop, manufacture and commercialize SEL24/MEN1703.
- learn more
- Acute Myeloid Leukemia
- Menarini Group
- A Phase I/II Study of SEL24 in Patients With Acute Myeloid Leukemia
Immuno-oncology & Immunometabolism
Ryvu Therapeutics has deep expertise in the discovery of small molecule candidates with optimized properties to address specific limitations of existing therapeutic approaches.
To identify these candidates, Ryvu uses platforms based on the most current understanding of how the immune system interacts with cancer cells and how cancer cells function biologically. These immuno-oncology and immunometabolism approaches have a successful history in biopharmaceutical development. Ryvu has accumulated scientific and technical infrastructure that allow high-throughput generation of candidates using these platforms.
Accumulation of adenosine is a potent and widespread mechanism that allows the tumor to evade immune surveillance. Adenosine suppresses activation, expansion and cytokine production in many types of immune cells, such as T cells, NK...
STING protein is one of the major players in innate immune activation being a potent trigger of type I interferon (IFN) and pro-inflammatory cytokines. STING agonists facilitate cancer antigen recognition specific to individual patient and...
The high therapeutic potential of HPK1 inhibitors (hematopoietic progenitor kinase 1, MAP4K1) lies in their potential to simultaneously improve T cell function, tumor antigen presentation and combat the immunosuppressive tumor microenvironment. HPK1 is a negative...
Accumulation of adenosine is a potent and widespread mechanism that allows the tumor to evade immune surveillance. Adenosine suppresses activation, expansion and cytokine production in many types of immune cells, such as T cells, NK cells or dendritic cells. Adenosine also switches macrophage polarization towards M2. Depending on cell type, adenosine signals through A2A or A2B receptor. Targeting both receptor subtypes by a dual inhibitor is a most effective strategy to counteract the adenosine related immune suppression in tumor.
Best-in-class dual A2A/A2B antagonists discovered by Ryvu target nearly all key subtypes of the immune cells involved in the immune response to cancer. Dual receptor profile and efficacy in both receptors maintained at very high adenosine levels differentiate Ryvu program from other adenosine receptor antagonists in development.
Ryvu plans to initiate clinical trials for the project in early 2021.
- Adenosine signals through two receptor subtypes (A2A and A2B) and reaches high levels in tumor microenvironment.
- Ryvu approaches clinical development of well differentiated best-in-class dual A2A/A2B antagonist.
- Published data supports combination potential with multiple standard of care approaches (immune checkpoint inhibitors, chemotherapy, radiation).
MECHANISM OF ACTION
- Best-in-class dual A2A/A2B antagonists.
- Low-/Subnanomolar potency maintained even in very high adenosine.
- Efficacy against adenosine mediates immune suppression demonstrated in several subpopulations of immune cells.
Leone et al., Targeting adenosine for cancer immunotherapy. J Immunother Cancer. 2018 Jun 18;6(1):57 doi: 10.1186/s40425-018-0360-8
Vijayan et al. Targeting immunosuppressive adenosine in cancer. Nat Rev Cancer. 2017 Dec;17(12):709-724. doi: 10.1038/nrc.2017.86.
Allard et al. Targeting the CD73-adenosine axis in immuno-oncology. Immunol Lett. 2019 Jan;205:31-39. doi: 10.1016/j.imlet.2018.05.001.
Sek et al. Targeting Adenosine Receptor Signaling in Cancer Immunotherapy. Int J Mol Sci. 2018 Dec 2;19(12). pii: E3837. doi: 10.3390/ijms19123837.
STING protein is one of the major players in innate immune activation being a potent trigger of type I interferon (IFN) and pro-inflammatory cytokines. STING agonists facilitate cancer antigen recognition specific to individual patient and his own tumour giving a hope for highly personalized immunotherapy. Additionally, STING agonists promote tumour infiltration by CD8+ T cells, immune system mobilization and long-term memory. The agents kill malignant cells and simultaneously convert them into a cancer-specific therapeutic vaccine.
- Formation of an active STING dimer results in recruitment and activation of TBK1, which subsequently leads to the phosphorylation of IRF3 and induction of type I interferon expression
- Small molecule, direct STING agonists of non-nucleotide, non-macrocyclic structure potent across species and STING human haplotypes
- Multiple possibilities of systemic delivery
Woo, S-R. et al, STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors (2014) 41(5): 830-42, Immunity doi:10.1016/j.immuni.2014.10.017
Corrales, L. et al, Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity (2015) 11(7): 1018-30, Cell Reports doi:10.1016/j.celrep.2015.04.031
The high therapeutic potential of HPK1 inhibitors (hematopoietic progenitor kinase 1, MAP4K1) lies in their potential to simultaneously improve T cell function, tumor antigen presentation and combat the immunosuppressive tumor microenvironment. HPK1 is a negative regulator of TCR-induced T cell activation and loss of HPK from dendritic cells endows them with superior antigen-presenting properties. Therefore, inhibition of HPK1 kinase activity with a small molecule may activate the superior anti-tumor activity and could address several key challenging factors in current immunotherapy (resistance in tumor microenvironment, impaired immune evasion with dysfunctional T effector cells) synergizing with immune checkpoints.
- HPK1 alters ERK/MAPK pathway, negatively regulating TCR-induced IL-2 production, maturation and proliferation of lymphocytes T
- HPK1 is critical for prostaglandin E2-mediated suppression of the anti-tumor response
- Potent HPK1 inhibitors with superior selectivity against MAP4K family and kinases engaged in TCR signalling
- Superior activators of dendritic cells and lymphocytes T resistant to PGE-2 mediated immunosuppression across multiple immune cells of human and mouse origin
Hernandez et al, The kinase activity of hematopoietic progenitor kinase 1 is essential for the regulation of T cell function (2018) 25:80–94, Cell Reports doi.org/10.1016/j.celrep.2018.09.012
Hematopoietic progenitor kinase 1 negatively regulates T cell receptor signaling and T cell–mediated immune responses (2007) 8:84-91doi:10.1038/ni1416
One of the challenges in the development of new oncology therapeutics is the limited number of protein targets known to be addressable with small molecules. Synthetic lethality allows the identification of novel protein targets and mechanisms of cancer cell sensitivity that can be used therapeutically.
Compounds active on specific synthetic lethal targets selectively kill tumor cells of a precisely defined model system, characterized by a specific genetic, epigenetic or metabolic characteristic. This is the approach actively investigated at Ryvu that allows the generation of compounds with highly specific and well-characterized activity.
Ryvu’s develops drugs for genetically determined cancers which had been considered in the past as largely undruggable using rational approaches. Synthetic lethality allows now for identification of novel unanticipated protein targets, highly effective in a...
Deletion of 9p21 locus is one of the most frequent genetic alterations associated with human cancers. Apart from tumor suppressor p16, locus 9p21 contains the gene coding methylthioadenosine phosphorylase (MTAP), the only enzyme capable of...
Ryvu’s develops drugs for genetically determined cancers which had been considered in the past as largely undruggable using rational approaches. Synthetic lethality allows now for identification of novel unanticipated protein targets, highly effective in a defined genetic context. Synthetic lethality has been utilized by Ryvu for targeting cancers with recurrent mutations in the chromatin remodeler complex SWI/SNF, present in over 20% of all solid tumors. Damaging mutations in SMARCA4 (BRG-1) – helicase/ATP subunit of the complex occur in nearly 10% of all non-small cell lung cancer (NSCLC- accounting for approximately 80 percent of all diagnosed cases). SMARCA2/BRM helicase has been identified as a synthetic lethal target in SMARCA4 mutated cells. Several strategies are used to develop novel drugs active in SMARCA4 deficient patients, such as small molecule inhibitors of BRM helicase activity, selective BRM degraders and compounds with a novel mode of action identified by the phenotypic approach. Active compounds developed by Ryvu selectively kill SMARCA4 deficient cells.
- Recurrent SWI/SNF mutations present in ~20% of solid cancers are damaging and not druggable directly
- So far no rational therapeutic options for nearly 10% of NSCLC with damaging SMARCA4 mutations
- SMARCA2/ BRM helicase identified as a synthetic lethal target in SMARCA4 deficient cancers
- Parallel development of BRM inhibitors, BRM degraders and novel modalities active in SMARCA4 deficient cells
- Ryvu applied an innovative synthetic lethality workflow, including proprietary data analysis engine, for identification of targets in cancers driven by undraggable oncogenes
- Identified novel synthetic lethal target are highly effective in the context of cancer- specific mutations
- Rational design of high-specificity BRM helicase inhibitors is a primary strategy in SMARCA4- deficient cancers
- Identified high- potency allosteric inhibitors of BRM engage the target and kill SMARCA4 deficient cells in nM range
- Alternative approach demonstrated using proprietary compounds degrading BRM in a proteolytic way
- High throughput phenotypic screen resulted in compounds selectively targeting SMARCA4 deficient cells by a novel mode of action
- Molecular profiling using next generation sequencing approaches (RNAseq, ChIPseq) allows for deconvolution of on-target activities for best application of identified molecules in the clinics
- Ashworth, Alan, and Christopher J Lord, ‘Synthetic Lethal Therapies for Cancer ’:, Nature Reviews Clinical Oncology, 2018 https://doi.org/10.1038/s41571-018-0055-6
- Bragelmann, J., N. Klumper, Anne Offermann, A. von Massenhausen, D. Bo hm, M. Deng, and others, ‘Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer’, Clinical Cancer Research, 2016 https://doi.org/10.1158/1078-0432.CCR-16-0094
- Hoffman, Gregory R, Rami Rahal, Frank Buxton, Kay Xiang, Gregory McAllister, Elizabeth Frias, and others, ‘Functional Epigenetics Approach Identifies BRM/SMARCA2 as a Critical Synthetic Lethal Target in BRG1-Deficient Cancers.’, Proceedings of the National Academy of Sciences of the United States of America, 111 (2014), 3128–33 https://doi.org/10.1073/pnas.1316793111
- Oike, Takahiro, Hideaki Ogiwara, Yuichi Tominaga, Kentaro Ito, Osamu Ando, Koji Tsuta, and others, ‘A Synthetic Lethality-Based Strategy to Treat Cancers Harboring a Genetic Deficiency in the Chromatin Remodeling Factor BRG1.’, Cancer Research, 73 (2013), 5508–18 https://doi.org/10.1158/0008-5472.CAN-12-4593
- Vangamudi, Bhavatarini, Thomas a Paul, Parantu K Shah, Maria Kost-Alimova, Lisa Nottebaum, Xi Shi, and others, ‘The SMARCA2/4 ATPase Domain Surpasses the Bromodomain as a Drug Target in SWI/SNF Mutant Cancers: Insights from CDNA Rescue and PFI-3 Inhibitor Studies.’, Cancer Research, 2015 https://doi.org/10.1158/0008-5472.CAN-14-3798
Deletion of 9p21 locus is one of the most frequent genetic alterations associated with human cancers. Apart from tumor suppressor p16, locus 9p21 contains the gene coding methylthioadenosine phosphorylase (MTAP), the only enzyme capable of degrading methylthioadenosine (MTA). MTAP deletion results in the accumulation of MTA in cells, which causes inhibition of PRMT5 methyltransferase, a decrease in the level of symmetrical dimethylation of arginine in proteins, and thus increased sensitivity to modulation of PRMT5 methylosome activity. In 2016, several functionally related biological targets synthetically-lethal in context of MTAP deletion were proposed. This means that MTAP-deletion of cancer cells is particularly sensitive to inhibition of these proteins and gives hope for creating a targeted therapy for a huge population of cancer patients (up to 15%).
- Targeting cells sensitized by MTAP deletion may provide targeted treatment option for vast patient population across many cancer types.
- In some tumor types (e.g. GBM or mesothelioma) >40% of patients may be sensitive.
- Highly competitive field with programs still in very early development stage.
MECHANISM OF ACTION
- Novel target discovery based on phenotypic approach.
- Risk balancing with concurrent fast follower approach.
- Lead stage planned in 2020.
Mavrakis et al., Disordered methionine metabolism in MTAPCDKN2A deleted cancers leads to dependence on PRMT5. Science. 2016 Mar 11;351(6278):1208-13. doi: 10.1126/science.aad5944.
Kryukov et al., MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science. 2016 Mar 11;351(6278):1214-8. doi: 10.1126/science.aad5214.
Marjon et al., MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A/PRMT5/RIOK1 Axis. Cell Rep. 2016 Apr 19;15(3):574-587. doi: 10.1016/j.celrep.2016.03.043.
Beyond publicly disclosed programs, Ryvu is working on candidates that address novel targets in the areas of synthetic lethality, immuno-oncology and immunometabolism to generate new therapeutics with first-in-class or best-in-class potential.
For the candidates, Ryvu is utilizing a proprietary drug discovery approach combining internally developed expertise and new sophisticated tools and technologies to identify small molecule compounds with favorable profiles and activity.
In 2013, Ryvu and Merck KGaA initiated a joint research strategy involving intensive work on multiple targets and several chemical series. The collaboration has successfully completed two milestones and has been expanded over time with additional targets.
The aim of the partnership with Merck is the development of new anticancer therapeutics acting on diverse biological targets associated with aberrant metabolic pathways in cancer cells. Dependence on specific metabolic pathways is a feature of various types of cancer, therefore, targeting this vulnerability has many potential applications in a broad range of patient populations.
The collaboration has resulted in scientific achievements, the joint filing of patent applications and data presentations at international scientific conferences.
Synthetically Lethal Interactions of Heme Oxygenase-1 and Fumarate Hydratase Genes, Biomolecules 2020
Podkalicka, P.; Mucha, O.; Kruczek, S.; Biela, A.; Andrysiak, K.; Stępniewski, J.; Mikulski, M.; Gałęzowski, M.; Sitarz, K.; Brzózka, K.; Józkowicz, A.; Dulak, J.; Łoboda, A. Synthetically Lethal Interactions of Heme Oxygenase-1 and Fumarate Hydratase Genes. Biomolecules 2020, 10, 143.
61st American Society of Hematology (ASH) Annual Meeting, December 7-10, 2019, Orlando, FL, USA
"SEL120 – a First-in-Class CDK8/19 Inhibitor As a Novel Option for the Treatment of Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome – Data from Preclinical Studies and Introduction to a Phase Ib Clinical Trial"
"CDK8 Inhibitors Induce Transcriptional Reprogramming of AML Cells Associated with Differentiation"
Society for Immunotherapy of Cancer 34th Annual Meeting (SITC 2019), November 6–10, National Harbor, MD, USA
"Novel dual A2A /A2B adenosine receptor antagonists for cancer immunotherapy in vitro characterization"
"Development and characterization of next generation small molecule STING agonists"